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Prediction and dissection of widely-varying association rate constants of actin-binding proteins.

ABSTRACT: Actin is an abundant protein that constitutes a main component of the eukaryotic cytoskeleton. Its polymerization and depolymerization are regulated by a variety of actin-binding proteins. Their functions range from nucleation of actin polymerization to sequestering G-actin in 1?1 complexes. The kinetics of forming these complexes, with rate constants varying at least three orders of magnitude, is critical to the distinct regulatory functions. Previously we have developed a transient-complex theory for computing protein association mechanisms and association rate constants. The transient complex refers to an intermediate in which the two associating proteins have near-native separation and relative orientation but have yet to form short-range specific interactions of the native complex. The association rate constant is predicted as k(a)?=?k(a0) e(-?G(el*)/k(B)T), where k(a0) is the basal rate constant for reaching the transient complex by free diffusion, and the Boltzmann factor captures the bias of long-range electrostatic interactions. Here we applied the transient-complex theory to study the association kinetics of seven actin-binding proteins with G-actin. These proteins exhibit three classes of association mechanisms, due to their different molecular shapes and flexibility. The 1000-fold k(a) variations among them can mostly be attributed to disparate electrostatic contributions. The basal rate constants also showed variations, resulting from the different shapes and sizes of the interfaces formed by the seven actin-binding proteins with G-actin. This study demonstrates the various ways that actin-binding proteins use physical properties to tune their association mechanisms and rate constants to suit distinct regulatory functions.

SUBMITTER: Pang X

PROVIDER: S-EPMC3464195 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Prediction and dissection of widely-varying association rate constants of actin-binding proteins.

Pang Xiaodong X Zhou Kenneth H KH Qin Sanbo S Zhou Huan-Xiang HX

PLoS computational biology 20121004 10

Actin is an abundant protein that constitutes a main component of the eukaryotic cytoskeleton. Its polymerization and depolymerization are regulated by a variety of actin-binding proteins. Their functions range from nucleation of actin polymerization to sequestering G-actin in 1∶1 complexes. The kinetics of forming these complexes, with rate constants varying at least three orders of magnitude, is critical to the distinct regulatory functions. Previously we have developed a transient-complex the ...[more]

PMID: 23055910

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Project description:The four cytokines erythropoietin (EPO), interleukin-4 (IL4), human growth hormone (hGH), and prolactin (PRL) all form four-helix bundles and bind to type I cytokine receptors. However, their receptor-binding rate constants span a 5000-fold range. Here, we quantitatively rationalize these vast differences in rate constants by our transient-complex theory for protein-protein association. In the transient complex, the two proteins have near-native separation and relative orientation, but have yet to form the short-range specific interactions of the native complex. The theory predicts the association rate constant as k(a)=k(a0)exp(-ΔG(el)(∗)/k(B)T) where k(a0) is the basal rate constant for reaching the transient complex by random diffusion, and the Boltzmann factor captures the rate enhancement due to electrostatic attraction. We found that the vast differences in receptor-binding rate constants of the four cytokines arise mostly from the differences in charge complementarity among the four cytokine-receptor complexes. The basal rate constants (k(a0)) of EPO, IL4, hGH, and PRL were similar (5.2 × 10(5) M(-1)s(-1), 2.4 × 10(5) M(-1)s(-1), 1.7 × 10(5) M(-1)s(-1), and 1.7 × 10(5) M(-1)s(-1), respectively). However, the average electrostatic free energies (ΔG(e1)(∗)) were very different (-4.2 kcal/mol, -2.4 kcal/mol, -0.1 kcal/mol, and -0.5 kcal/mol, respectively, at ionic strength=160 mM). The receptor-binding rate constants predicted without adjusting any parameters, 6.2 × 10(8) M(-1)s(-1), 1.3 × 10(7) M(-1)s(-1), 2.0 × 10(5) M(-1)s(-1), and 7.6 × 10(4) M(-1)s(-1), respectively, for EPO, IL4, hGH, and PRL agree well with experimental results. We uncover that these diverse rate constants are anticorrelated with the circulation concentrations of the cytokines, with the resulting cytokine-receptor binding rates very close to the limits set by the half-lives of the receptors, suggesting that these binding rates are functionally relevant and perhaps evolutionarily tuned. Our calculations also reproduced well-observed effects of mutations and ionic strength on the rate constants and produced a set of mutations on the complex of hGH with its receptor that putatively enhances the rate constant by nearly 100-fold through increasing charge complementarity. To quantify charge complementarity, we propose a simple index based on the charge distribution within the binding interface, which shows good correlation with ΔG(e1)(∗). Together these results suggest that protein charges can be manipulated to tune k(a) and control biological function.

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Prediction and dissection of widely-varying association rate constants of actin-binding proteins.

Publications

Prediction and dissection of widely-varying association rate constants of actin-binding proteins.

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